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Background  Previous results showed that over-expression of the  WTH3  gene in MDR cells reduced  MDR1  gene expression and converted their resistance to sensitivity to various anticancer drugs. In addition, the  WTH3  gene promoter was hypermethylated in the MCF7/AdrR cell line and primary drug resistant breast cancer epithelial cells.  WTH3  was also found to be directly targeted and up regulated by the  p53  gene. Furthermore, over expression of the  WTH3  gene promoted the apoptotic phenotype in various host cells.    Methods  To further confirm  WTH3 's drug resistant related characteristics, we recently employed the small hairpin RNA (shRNA) strategy to knockdown its expression in HEK293 cells. In addition, since the  WTH3  promoter's p53-binding site was located in a CpG island that was targeted by methylation, we were interested in testing the possible effect this epigenetic modification had on the  p53  transcription factor relative to  WTH3  expression. To do so, the  in vitro  methylation method was utilized to examine the  p53  transgene's influence on either the methylated or non-methylated  WTH3  promoter.    Results  The results generated from the gene knockdown strategy showed that reduction of  WTH3  expression increased  MDR1  expression and elevated resistance to Doxorubicin as compared to the original control cells. Data produced from the methylation studies demonstrated that DNA methylation adversely affected the positive impact of  p53  on  WTH3  promoter activity.    Conclusion  Taken together, our studies provided further evidence that  WTH3  played an important role in MDR development and revealed one of its transcription regulatory mechanisms, DNA methylation, which antagonized  p53 's positive impact on  WTH3  expression.

Methylation of WTH3, a possible drug resistant gene, inhibits p53 regulated expression